- INTRODUCTION: THE FIRST MEDICAMENT THAT KILLS CANCER CELLS BUT NOT HEALTHY CELLS
- I. EFFICACY
- CASE REPORTS
- ANTIVIRAL PROPERTIES
- THE INHIBITION OF THE TUMORAL ANGIOGENESIS
- THE IN VIVO STUDIES
- MODULATION OF THE IMMUNE SYSTEM
- RADIOPROTECTIVE EFFECT
- TOXICOLOGIC STUDIES
- NORMALISATION OF THE METABOLISM
- THE EFFECT ON VARIOUS ENZYMES
- INTERACTION WITH OTHER DRUGS
- II. SAFETY
- III. QUALITY
When NSC 631570 has been used in clinic, it was observed that the patients treated with this drug tolerate the concomitant radiotherapy much better. The adverse effects of this aggressive treatment modality were significantly reduced to minimal. This gave reason to study radioprotective properties of NSC 631570 in the in vitro and in vivo tests.
To evaluate whether the radio protective effect of NSC 631570 originates from its raw materials, the tests in mice with various radiation doses were performed at the Research Institute of Military Medicine, St. Petersburg, Russian Federation. It was proven the radioprotective effect of NSC 631570 was far superior compared to such of its raw materials taken separately, both measured by survival of mice irradiated by different doses and by the protection coefficient. For example, at a dose of 5.25 Gy protection coefficient of NSC 631570 was 95.0 ± 4.6 vs 50.8 ± 4.6 in the control. These observations suggested that the radio protective effect of Ukrain differs significantly from such of its raw materials (132).
Further studies showed NSC 631570 to modulate the cell components of the hemopoietic system (stem cells, proliferating, maturing, and competent cells) so that their total radioresistance increases. In the study aiming to describe qualitative and quantitative changes in hemopoietic precursor cells and in myelokaryocytes and leukocytes in the blood, Ukrain was administered intraperitoneally to mice at a dose of 0.2 mg/kg. Control animals were injected with normal saline. Colony-forming units (CFU) were counted in the spleen and bone marrow of the mice, and myelokaryocyte and leukocyte (Iymphocyte and granulocyte) counts were determined. The results of this study suggest that Ukrain causes qualitative and quantitative alterations in different pools of hemopoietic cells (stem cells, proliferating cells, maturing cells, and competent cells). These alterations affect the size of the stem cell pool, the kinetics of stem cell proliferation, the direction of their differentiation pathways, the rate of circulation of stem cells and precursor cells, the efficiency of recolonization of cell-depleted sites, and other parameters, which in turn modify standard responses of hemopoiesis and immunogenesis to irradiation so that the radioresistance of the whole organism increases (77, 133, 249).
The radioprotective effect of NSC 631570 has been confirmed by the infection models in mice where its effect was superior to the effect of the known radioprotector cysteamine (134).
Compared to other agents, NSC 631570 exerted a strong radioprotective effect similar to such of lymphokinin. In this study, the effects of the preventive administration of cysteamine, naphthysin, Ukrain, lymphokinin, prodigiosan, and polyribonate on the 30-day survival of mice subject to doses of ionizing radiation were compared. Conventional radioprotectors were shown to prevent the death of experimental animals irradiated with doses ranging from LD50/30 to LD100/30 but were inefficient as a means of preventing mortality at doses with a medium lethal effect. In contrast, the bioregulators Ukrain and lymphokinin were more potent at doses ranging from LD50 to LD70/30 (1.5 times more potent than conventional radioprotectors). Polyribonate and prodigiosan were the least potent. The authors assumed the radioprotective effect of Ukrain as ‘strong’ (135).
These radioprotective properties of NSC 631570 were confirmed in further studies in rats at the Institute of Applied Cell Culture (Munich, Germany). After peritoneal administration, Ukrain had no effect on the concentration of thyroid hormones in rat blood and increased the concentration of thyroid hormone receptors in the liver of intact rats during the first two months after administration. Ukrain normalized the level of nuclear thyroid hormone receptors influenced by short-term whole body gamma-irradiation of rats with 1 Gy, beginning from the first day after administration of the drug. Thus, authors concluded Ukrain can minimize the consequences of irradiation on the endocrine system of experimental animals (172).
Administered intraperitoneally, NSC 631570 exerted a protective effect on the hormonal system of irradiated female rats. Ukrain caused the normalization of the intracellular glucocorticoid receptor system, affected by short-term whole-body gamma-irradiation of rats with 1 Gy beginning on the 10th day after administration of the drug. It was found that Ukrain minimized the consequences of irradiation in the endocrine system of the experimental animals (173).
The radio protective effect of NSC 631570 was also studied and confirmed on in vitro models on the human skin firbroblasts HSF1 and HSF2 as well as lung fibroblasts CCD32-LU. As evaluation parameters were chosen cytotoxicity, apoptosis induction, cell cycle course, and the expression of TP53 and p21. Additionally, following malignant cell lines were used: MDA-MB-231 (human breast tumor), PA-TU-8902 (pancreas cancer), CCL-221 (colorectal cancer), and U-138MG (glioblastoma). The cytotoxicity of NSC 631570 was time- and dose dependent. The combination of NSC 631570 plus ionizing radiation (IR) enhanced toxicity in CCL-221 and U-138MG cells, but not in MDA-MB-231 and PA-TU-8902 cells. Most strikingly, a radioprotective effect was found in normal human skin and lung fibroblasts. Flow cytometry analyses supported differential and cell line-specific cytotoxicity of NSC 631570. CCL-221 and U-138MG cells accumulated in G2 after 24h treatment with NSC 631570, whereas no alterations were detected in the other tumor cells and normal fibroblasts tested. Differential effects of NSC 631570 in modulating radiation toxicity of human cancer cell lines and its protective effect in normal human fibroblasts suggest that this agent may be beneficial for clinical radiochemotherapy (184).
In their next study on the role of the proteins fibronectin and laminin in the radiation protection mechanisms of the cells, the researchers from the University of Tübingen used NSC 631570 as a reference substance (198).
NSC 631570 was effective in the therapy of recurring respiratory diseases in children from the Chernobyl area. A total of 38 children from areas radiation contaminated after the Chernobyl accident and suffering from recurrent respiratory diseases were included into the study. Ukrain was administered intravenously at a dose of 5 mg twice a week, up to a total dose of 35 mg. The control group received standard therapy. In the Ukrain treated group marked anti-inflammatory effects was revealed comparing to the control: normalisation of WBC count and blood sedimentation rate. The immune modulating effect of Ukrain was indicated through the improvement in specific humoral and cellular immunity: increased the IgG concentration, the phagocytic activity of neutrophils, the number of total lymphocytes, T-lymphocytes and T-helpers, and the helpers/suppressors ratio (202).